1. Field of the Invention
The present invention relates to an adhesive hemostatic agent free of blood constituents, which is useful in surgical operations, and a method for the production thereof.
Porcine collagen is used as an active ingredient of the adhesive hemostatic agent. In order to be used, porcine collagen is rendered non-immunogenic by removing telopeptides therefrom. The resulting atelocollagen is esterified to give positive charges thereon, which enable the collagen to bind faster to negatively charged platelets, thus eliciting haemostasis quickly. In addition, 3,4-dihydroxy-phenyl alanine (hereinafter referred to as “DOPA”), highly adhesive to plasma proteins, when in a salt solution, can ensure high adhesive strength and blood coagulation activity for the collagen-based adhesive hemostatic agent. Further, an antifibrinolytic may be added in a trace amount to the collagen-based adhesive hemostatic agent.
Based on the fact that blood coagulation starts when platelets bind to collagen, the ubiquitous extracellular matrix, the present invention contemplates a collagen-based adhesive hemostatic agent greatly improved in anti-hemorrhage and tissue sealing activity and a method for preparing the same. Instead of bovine collagen, porcine collagen, free of TSE's (Transmissible Spongiform Encephalopathies), is made non-immunogenic by the removal of telopeptides therefrom, and the carboxylic acid groups of the non-immunogenic collagen are esterified with ethanol such that the atelocollagen is positively charged and thus can bind quickly to negatively charged platelets, inducing haemostasis quickly. In addition, the use of DOPA (3,4-dihydroxy-phenyl alanine), functioning to stabilize collagen fibers, in combination with salt and an antifibrinolytic ensures excellent adhesive strength and tissue sealing activity for the collagen-based adhesive hemostatic agent.
2. Description of Related Art Including Information Disclosed Under 37 CFR 1.97 and 37 CFR 1.98
Haemostatis and tissue gluing are very important in surgical operations because they lead to fast post-operative healing of wounds and tissue sealing. Like ‘Beriplast P’ (Aventis)™, ‘Greenplast kit’ (Green Cross)™, ‘Tisseel kit’ (Baxter AG)™, ‘Tissucol Duo Quick’ (Baxter AG)™, ‘TachoSil’ (Nycomed)™ and ‘Tachocomb’ (Nycomed)™, most conventional haemostatic bio-glues or bio-adhesives employ blood constituents such as fibrinogen, thrombin, etc., and thus are based on the blood coagulation process in which thromboplastin, together with calcium, activates prothrombin to thrombin, which in turn converts fibrinogen into fibrin which is cross-linked in the presence of transglutaminase (Factor XIII) to form fibrin clots. Because the basic materials of the conventional haematostatic bio-glues or bio-adhesives are derived from blood constituents and have the possibility of being infected with viruses such as HIV, HBV, HCV and CMV, strict regulations are imposed on the preparation of the haemostatic bio-glues or bio-adhesives as well as the securing and storing of the basic materials.
Particularly, the haematostatic products ‘Greenplast kit’™, ‘Tisseel kit’™, ‘Tissucol Duo Quick’™, and ‘Tachocomb’™ additionally contain aprotinin, a protein isolated from bovine lung, as an antifibrinolytic, but cause anaphylaxis or a severe allergic reaction though at a very low rate.
Recently, hemostatic agents based on non-blood constituents have been developed and are commercially available, like ‘Avitene’ (Alcon)™ and ‘Helitene’ (Duhamed)™. However, having single collagen components, they are very expensive and are used for hemostatic agent only due to their lacking a tissue gluing activity.
Other hemostatic agents can be found in U.S. Pat. No. 5,464,471 entitled “Fibrin Monomer Based Tissue Adhesive”, 1995, U.S. Pat. No. 5,883,078 entitled “Hemostatic and Tissue Adhesive”, 1999, U.S. Pat. No. 5,773,033, entitled Fibrinogen/chitosan hemostatic agents”, 1998, U.S. Pat. No. 5,605,887 entitled “Therapeutic Fibrinogen Compositions”, 1997. Likewise, these agents employ blood constituents including fibrinogen, thrombin, coagulants, aprotinin, bovine proteins and the like, thus raising concerns about contamination with particular pathogens and excessive costs for securing and storing materials and preparing the products. Conventional non-blood hemostatic agents employing collagen show anti-hemorrhage effects only, but do not function as tissue adhesives.